tbuckley/cabot-search huggingface dataset:
A phase II, multicenter, single-arm study of parsaclisib, a PI3Kδ inhibitor, in relapsed or refractory follicular lymphoma in China: Updated data from the study.
Authors: Zhong Zheng, Huilai Zhang, Keshu Zhou, Hui Zhou, Li Zhang, Caixia Li, Min Zhou, Wenbin Qian, Zhiming Li, Qingyuan Zhang, Ying Cheng, Peng Liu, Zhenyu Li, Liping Su, Fei Li, Xiuhua Sun, Jingwen Wang, Yuhuan Gao, Xielan Zhao, Weili Zhao
Journal: Journal of Clinical Oncology (2022)

7574 Background: For Follicular lymphoma (FL) patients (pts) of 3 rd or higher line, treatment options are limited. Parsaclisib is a potent, highly-selective, next-generation PI3Kδ inhibitor. Initial safety and efficacy data were previously presented (Zhong Zheng et al. ASH 2021; NCT04298879). Here, we report safety, efficacy and survival data of the multicenter, open-label phase 2 study of parsaclisib in 3 rd or higher line FL pts in China. Methods: Key eligibility included, age ≥ 18 years, histologically confirmed FL grade 1, 2, or 3a, ≥ 2 prior systemic therapies, ECOG PS ≤ 2, and ineligible for hematopoietic stem cell transplantation (HSCT). Pts received parsaclisib 20 mg once daily (QD) for 8 weeks followed by 2.5 mg QD, till disease progression (PD), unacceptable toxicity, death or withdrawn consent. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Primary endpoint was objective response rate (ORR) evaluated by an Independent Review Committee (IRC) according to Lugano 2014 criteria, secondary endpoints included: duration of response (DOR), PFS, OS, and safety and tolerability. Results: As of the data cutoff date (Dec 12, 2021), 61 pts (median age: 50yr; male [n = 35, 57.4%]) were enrolled. Forty-eight pts remained on treatment and 13 pts had discontinued study treatment mainly due to PD (n = 11). With a median follow-up time 9.5 months (range 6.0-19.7months), the median duration of treatment was 251.0 days (range: 23.0-589.0 days). All 61 pts were evaluable for response, the ORR and complete response rate (CRR) were 86.9% (n = 53, 95% CI: 75.8-94.2%) and 31.1% (n = 19, 95% CI: 19.9-43.3%), respectively. The median time to response (TTR) was 8.0 weeks (95% CI: 7.9-8.0%), and the median DOR was not reached (95% CI: 9.2 months-NC), and 43 of 53 pts with CR or PR still retained CR or PR. As data cutoff, eleven (17.9%) pts had disease progression, the median PFS was not achieved. Three pts died data as data cutoff, the median OS was not achieved. Among the 61 treated pts, 48 (95.1%) pts experienced at least 1 treatment-emergent adverse events (TEAEs), with the most common TEAEs being neutrophil count decreased (49.2%), white blood cell count decreased (32.8%). Twenty-seven patients (44.3%) experienced grade ≥ 3 TEAEs, the most common grade ≥ 3 TEAEs was neutrophil count decreased (n = 10, 16.4%). Conclusions: Parsaclisib demonstrated promising efficacy, and acceptable safety profile. These results suggest that parsaclisib could benefit 3 rd or higher line Follicular lymphoma patients. Clinical trial information: NCT04298879.
Serum cytokines could be predictors for PD-1 antibody response in advanced HBP cancer.
Authors: Shengmin Mei, Zenglei He, Bin Wang, Liang Xue, Li Xu, Qi Ling
Journal: Journal of Clinical Oncology (2022)

e16114 Background: According to previous clinical trials and pilot studies, PD1 antibodies might provide favorable long-term survival in combination with chemotherapy for unresectable hepatobiliary and pancreatic (HBP) cancers. We conducted a real-world evaluation of PD1 antibodies in patients with unresectable HBP cancers. We also aimed to explore biomarkers for the early prediction of PD1 antibodies response. Methods: From Jan 2021 to Dec 2021, 48 unresectable HBP cancers were enrolled in Yuhang campus, the first affiliated hospital, Zhejiang university school of medicine. The key eligibility criteria were:(1)histopathologically confirmed advances unresectable HBP cancers; (2)without systematic treatment; (3)¡Ý18 years old; (4)ECOG PS 0 or 1. Clinical decisions were made by multi-disciplinary team (MDT). The treatment efficacy was evaluated by mRECIST. Results: A total of 48 patients were finally included and analyzed, which their baseline characteristics were listed in Table. we assessed the treatment efficacy using the dynamic change of tumor makers. And we observed that tumor markers of progressive disease(PD) group were higher than those of stable disease(SD) and partial response(PR) group. A total of 37 patients with complete biomarker data, were finally included in cytokines and immune response analysis. During the immune checkpoint inhibitors treatment, we detect the trough concentration of serum cytokines(IL-2, IL-4, IL-6, IL-10, IL-16, TNF-¦Á and TIFN-¦Ã). We observed that serum cytokines indexes of PD group were higher than those of SD and PR group. Conclusions: We observed that tumor markers of PD group were higher than those of SD and PR group. The serum cytokines (IL-4, IL-16 and TIFN-¦Ã) may be potential biomarkers for the early prediction of PD1 antibodies response. [Table: see text]
Treatment interruptions and discontinuations among patients with stage III unresectable non–small cell lung cancer treated with durvalumab at the Veterans Health Administration.
Authors: Munaf Alkadimi, Amanda Moore, Christopher R Frei, Kelly R Reveles, Lance Brannman, Ion Cotarla, Andrew Frankart, Tiernan Mulrooney, Paromita Datta, Jennifer Whitehead, Kathleen Franklin, Renee Reichelderfer, Madison H. Williams, Ryan A. Williams, Sarah Allison Smith, Xavier Jones, Zohra Nooruddin
Journal: Journal of Clinical Oncology (2022)

8554 Background: The PD-1/PD-L1 pathway is a mechanism of immune evasion and disruption of this pathway with immune checkpoint inhibitors (ICIs) has shown clinical benefit in multiple malignancies. Based on results from the PACIFIC trial, durvalumab is approved as consolidation therapy in patients (pts) with stage III unresectable non-small cell lung cancer (UR-NSCLC) without progression following concurrent chemoradiotherapy (cCRT). Durvalumab has been used extensively in Veterans Health Administration (VHA) facilities, providing an opportunity to evaluate durvalumab treatment interruptions (TI), treatment discontinuations (TD), and the reasons for these on a national scale. Methods: Patients with stage III UR-NSCLC receiving durvalumab consolidation immunotherapy at the VHA between January 1, 2017 and June 30, 2020 with a minimum follow up for 12 months were included using ICD-10, HCPCS, and J codes and followed from their durvalumab start date through the earliest of last VHA visit, loss to follow up, death, or end of study (excluded if durvalumab therapy was ongoing at the end of the study, because the full treatment course could not be determined). TI were defined as durvalumab infusions separated by &gt;28 days. Reasons for TI and TD are presented descriptively. Durations are reported using medians and interquartile ranges (IQR). Results: 935 pts were included (median age = 69 years; 95% males; 96% current or former smokers; 70% with COPD; histologies [squamous (50%), non-squamous (43%), other/missing (7%)]; and 77% with carboplatin-paclitaxel as their platinum-based CRT). Durvalumab TI were experienced by 19% of pts (median [IQR] number of TI = 1 [1-1], median [IQR] TI duration = 53 days [39-90]). The main reasons for TI were toxicity (8%) and social reasons (3%) (Table). The median duration of treatment (DoT) with durvalumab (TI included) was 9.0 months (IQR 2.9-11.8). Durvalumab TD occurred in 59% of pts. Top reasons for discontinuation across all 935 pts included disease progression (24%) and toxicity (18%) (Table). Conclusions: In this real world analysis of national VHA data, durvalumab DoT was similar to PACIFIC despite having a patient population with worse prognostic factors (e.g. more males, squamous, COPD) with 8% of VHA pts experiencing TI and 18% TD due to toxicity. Patients could benefit from additional efforts to prevent, identify, and manage toxicities in the UR-NSCLC population [Table: see text]
OTHR-10. Pilocytic astrocytoma with respect to treatment
Authors: Phua Hwee Tang, Sameema Nisa
Journal: Neuro-Oncology (2022)

Abstract AIM: To describe the sizes of pilocytic astrocytoma with respect to treatment Methodology Pediatric pilocytic astrocytomas cases from 2001 to 2021 were retrospectively reviewed in this Institutional Review Board approved study. Imaging reports, location of tumour, maximum dimension of tumour at diagnosis, treatment given (operation/chemotherapy/ radiotherapy), degree of tumor excision were captured. RESULTS: Imaging was available in 33 with 23 centered in the posterior fossa (1 extending into thalamus), 4 in suprasellar region, 2 in cerebral hemisphere, 2 in thalamus, 1 in pineal thalamic region and 1 in cervicomedullary spine, Tumor dimension at presentation was 5.40 cm ± 2.34 cm. Tumor size at presentation did not show significant correlation with age. 30 patients underwent operation with tumours completely excised in 15 and partially excised in 14 and no postoperative information for 1. Three patients, where tumour involved the thalamus, did not have operation and were given radiotherapy, average size of tumour being 3.47 + 1.15 cm. compared to the 5.59 + 2.34 size of tumours that underwent operation (p=0.06). Completely excised tumours measured 6.29 ± 2.04 cm at presentation while incompletely excised ones measured 4.76 ± 2.53 cm, not significantly different (p=0.09). Unoperated tumours are statistically smaller than those completely excised (p=0.02). One of the completetly excised tumours was located in the parietal cerebral hemisphere with the rest of the 15 in the posterior fossa. Seven of the incompletely excised tumours were located in the posterior fossa with 4 in suprasellar region, 1 in thalamus, 1 in spine and 1 in cerebral hemisphere. 3 patients with uncompletely excised tumours (1 cerebral, 1 post fossa, 1 spine) had post-operative radiation while 2 suprasellar tumours were given post-operative chemotherapy. CONCLUSION: Completely excised tumours are mainly located in posterior fossa. Tumours not operated on are located in thalamus and significantly smaller than tumours which are completely excised.
EPCT-03. Working together to accelerate the preclinical to clinical translation of drug delivery systems for children’s brain tumours
Authors: Emma Campbell, Kristian Aquilina, Madhumita Dandapani, David Walker, Ruman Rahman
Journal: Neuro-Oncology (2022)

Abstract Children's brain tumours are the biggest cancer killer in children and young adults. Several techniques, such as intra-cerebrospinal fluid chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems, electric field therapy, and intra-arterial and intra-nasal chemotherapy, have the potential to transform the treatment of brain tumours in children. However, there have been very few clinical trials to evaluate these. In 2021, the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) and the ITCC (Innovative Therapies for Children with Cancer) brain tumour group established a Clinical Trials Working Group comprising international researchers and clinicians to address this issue. This partnership highlighted the main challenges in preclinical to clinical translation of paediatric CNS drug delivery as: (1) a lack of specific funding for prototype development and/or scale-up for clinical trials; (2) difficulties in navigating the regulatory landscape; (3) lack of accurate preclinical models; and (4) increased need for multi-centric working. In response to this, we ran a hybrid workshop in November 2021 on ‘Clinical Trial Readiness for CNS Drug Delivery’. At this workshop, around 50 delegates (comprising clinicians, researchers, trial regulatory experts, policy makers, and representatives from funding organisations, brain tumour charities and industry) came together to discuss issues around funding, preclinical models and regulatory processes. We have established speciality-specific working groups to build on the workshop discussions, with the aim of producing recommendations around the use of preclinical models and drug delivery techniques according to brain tumour type. We have also used the workshop presentations and discussions to create a ‘Roadmap’ document for preclinical to clinical translation, which will be freely shared with the neuro-oncology research community. We continue to liaise with funders and regulatory bodies to address the changes that are needed in these areas. If you would like to join our network, contact: cbtddc@nottingham.ac.uk
In knee OA, PT vs. glucocorticoid injections had an incremental cost-effectiveness ratio of $35 527/QALY gained
Authors: Angelo L. Gaffo
Journal: Annals of Internal Medicine (2022)

Source Citation Rhon DI, Kim M, Asche CV, et al. Cost-effectiveness of physical therapy vs intra-articular glucocorticoid injection for knee osteoarthritis: a secondary analysis from a randomized clinical trial. JAMA Netw Open. 2022;5:e2142709. 35072722
Temporal and spatial dynamics in the regulation of myocardial metabolism during the ischemia-reperfusion process
Authors: E De Dios, C Rios Navarro, J Moya, J Gavara, N Perez-Sole, V Marcos-Garces, MJ Forteza, A Diaz, A Ruiz-Sauri, FJ Chorro, V Bodi
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by “Instituto de Salud Carlos III” and “Fondos Europeos de Desarrollo Regional FEDER” (grant numbers PI20/00637 and CIBERCV16/11/00486) and Conselleria de Educación – Generalitat Valenciana (PROMETEO/2021/008). Introduction In the context of severe myocardial ischemia, cardiac metabolism shifts from beta oxidation to glycolisis. However, the temporal and spatial dynamics of the main regulators of myocardial metabolism during the ischemia-reperfusion process in the infarcted heart has not been fully characterized. Methods Myocardial infarction (MI) was induced in swine by means of 90 minutes occlusion of the mid left anterior descending coronary artery using angioplasty balloons. Tetrazolium staining and intracoronary infusion of thioflavin-S were used to define the infarcted, adjacent, and remote areas. mRNA and protein expression of PGC1a, PPARa, ERRa, GLUT1, and GLUT4 were quantified in controls and in MI groups submitted to 48 hours and 3 weeks of reperfusion. Results Compared to controls, a severe and generalized drop of PGC1a mRNA gene and protein levels occurred in the infarcted, adjacent and remote areas since ischemia onset until 48 hours reperfusion that persists at 1 month in the infarcted region. Similar dynamics occurred in the infarcted, adjacent, and remote areas in the case of PPARa gene expresion; PPARa protein significantly decreased only until 48 hours reperfusion in the infarcted area. ERRa gene and protein expression persistenly decreased only in the infarcted region since ischemia onset until 1 month. Incrases in GLUT1 (since ischemia onset) and GLUT4 (at 1 month) were detected. Conclusions Dynamics and generalized changes in metabolism regulation to a shift from beta oxidation to glycolisis occur in the infarcted heart since ischemia onset until late after reperfusion. Further research in this field can be helpful for a better understanding of pathophysiology of myocardial infarction and to explore new therapeutic options.
Management of residual nonretroperitoneal disease in nonseminomatous germ-cell tumors (NSGCT).
Authors: Jennifer King, Kenneth Kesler, Ryan Ashkar, Sandra K. Althouse, Nasser H. Hanna, Lawrence H. Einhorn, Nabil Adra
Journal: Journal of Clinical Oncology (2022)

5034 Background: The management of NSGCT patients (pts) with post-chemotherapy residual non-retroperitoneal disease (RP) remains unsettled. Decisions for surveillance vs surgical resection are commonly steered by pathology from retroperitoneal lymph node dissection (RPLND). Data is limited in pts who do not require RPLND (normal or normalized RP post-chemo). Methods: The prospectively maintained Indiana University testicular cancer database was queried for pts with metastatic NSGCT who completed first-line chemotherapy and had residual extra-RP disease without residual RP disease. Pts with post-chemo non-RP surgical resection were included. Results: 134 pts met eligibility. Median age at diagnosis was 28.6 (range, 16.2-51.5). Primary tumor predominant histology was embryonal (35.1%), mixed (25.4%), seminoma (2.2%), yolk sac (9.7%), choriocarcinoma (15.7%), teratoma (11.2%). 76 pts (56.7%) had teratoma in the primary tumor. Metastatic sites at diagnosis were RP (15.7%), mediastinal LN (8.2%), lung (28.4%), liver (11.2%), bone (6.7%), brain (21.6%). Those with RP mets at diagnosis had normalization of RP nodes after chemo. IGCCCG risk was good in 57, intermediate in 21, and poor in 56 pts. Median pre-chemo AFP was 66 (0.9-467,000). hCG was 960.5 (0.5-1,300,000). First-line chemo was BEPX4 in 68, BEPx3 in 29, EPX4 in 10, VIPX4 in 9, and other in 18 pts. All pts had surgical resection of non-RP disease. None had RPLND. 84 pts had lung nodule resection, 16 had mediastinal LN, 8 had cervical LN, 5 had liver, 6 had bone, and 20 had brain met resection. Of the 76 pts with teratomatous elements in the orchiectomy, 41 (53.9%) had teratoma and 24 (31.6%) had non-teratoma GCT in post-chemo non-RP surgical specimens. Of the 58 pts without teratoma in the orchiectomy, 9 (15.5%) had teratoma and 34 (58.6%) had non-teratoma GCT in the non-RP surgical resection specimens. Teratoma in the orchiectomy was a predictor of non-RP teratoma (Fisher’s exact test P&lt;0.0001). Conclusions: The presence of teratoma in orchiectomy predicts teratoma in residual post-chemo non-RP disease in pts who do not undergo RPLND. The absence of teratoma in orchiectomy should not preclude resection of residual non-RP disease given a subset of patients had persistent GCT. [Table: see text]
Epi‐immunotherapy for cancers: rationales of epi‐drugs in combination with immunotherapy and advances in clinical trials
Authors: Yang Xu, Ping Li, Yang Liu, Dijia Xin, Wen Lei, Aibin Liang, Weidong Han, Wenbin Qian
Journal: Cancer Communications (2022)

Abstract Over the last two decades, several epi‐drugs, immune checkpoint inhibitors (ICIs) and adoptive cell therapies have received clinical approval for use in certain types of cancer. However, monotherapy with epi‐drugs or ICIs has shown limited efficacy in most cancer patients. Epigenetic agents have been shown to regulate the crosstalk between the tumor and host immunity to alleviate immune evasion, suggesting that epi‐drugs can potentially synergize with immunotherapy. In this review, we discuss recent insights into the rationales of incorporating epigenetic therapy into immunotherapy, called epi‐immunotherapy, and focus on an update of current clinical trials in both hematological and solid malignancies. Furthermore, we outline the future challenges and strategies in the field of cancer epi‐immunotherapy.
Landscape of fibroblast growth factor receptor (<i>FGFR</i>) genomic alterations (GA) in urothelial bladder cancer (UBC).
Authors: Maroun Bou Zerdan, Gennady Bratslavsky, Joseph M Jacob, Richard S.P. Huang, Oleksandr Kravtsov, Vamsi Parimi, Douglas I. Lin, Ryon Graf, Natalie Danziger, Jeffrey S. Ross, Hanan Goldberg, Alina Basnet
Journal: Journal of Clinical Oncology (2022)

4568 Background: Urothelial bladder carcinomas (UBC) with genomic alterations (GA) in the Fibroblast Growth Factor Receptor ( FGFR) genes have been postulated to be less responsive to immune checkpoint inhibitors (ICI). Immune microenvironment of these tumors could be altered due to suppression of interferon signaling pathways. Here, we present comprehensive genomic profiling (CGP) of FGFR altered UBC to study the underlying immunogenomic mechanisms of response and resistance. Methods: 4,035 UBC underwent hybrid capture based CGP. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined using 114 loci. Programmed death ligand (PD-L1) expression in tumor cells was assessed by IHC (Dako 22C3). Results: 894 (22%) of UBC featured FGFR GA ( FGFR1 3.7%; FGFR2 1.1%; FGFR3 17.4%). Gender and age distribution was similar in all groups. FGFR3 cases had lower GA/tumor and 14.7% GA were fusions. ERBB2 amplification was significantly higher in FGFR1/2 altered UBC compared with FGFR3 altered UBC. MTOR pathway GA were highest in FGFR3 altered UBC. FGFR3 altered UBC featured significantly higher frequencies of biomarkers predicting resistance to ICI including lower TMB, lower PD-L1 expression and higher frequencies of GA in MDM2. FGFR3 driven UBC also features significantly higher frequencies of CDKN2A/B loss and MTAP loss which have also recently been linked to IO drug resistance. Conclusions: UBC harboring FGFR GA have increased frequency of alterations that have been linked to ICI resistance. Further evaluation of FGFR-based biomarkers in UBC clinical trials focused on the assessment of the patient response to ICI appears warranted. [Table: see text]
SALVO: Single-arm trial of ipilimumab and nivolumab as adjuvant therapy for resected mucosal melanoma.
Authors: Lisa A. Kottschade, Gregory Russell Pond, Anthony J. Olszanski, Yousef Zakharia, Evidio Domingo-Musibay, Ralph J. Hauke, Brendan D. Curti, Sarah Schober, Mohammed M. Milhem, Matthew Stephen Block, Robert R. McWilliams
Journal: Journal of Clinical Oncology (2022)

9573 Background: Mucosal melanoma is a rare, highly aggressive form of melanoma with extremely high recurrence rates, despite definitive surgical resection. Median RFS has been reported to be 5.4m, with RFS rates at 1 and 2 years of 10%, and 0%, respectively (Lian B, Si L, Cui C, et al. Phase II Randomized Trial Comparing High-Dose IFN-α2b with Temozolomide Plus Cisplatin as Systemic Adjuvant Therapy for Resected Mucosal Melanoma. Clinical Cancer Research 2013, 19(16):4488-4498). Currently there is no consensus on recommendations for adjuvant therapy. Data on the use of immune checkpoint inhibitors (ICI) adjuvantly is lacking. Methods: We performed a single arm, multicenter clinical trial using “flip dose” ipilimumab (1mg/kg q3w x4 cycles),and nivolumab (3 mg.kg q3w x4 cycles), then Nivolumab 480 mg q4w x 11 cycles to complete a year of adjuvant therapy. The primary endpoint was recurrence-free survival (RFS), and the study had 85% power to detect an improvement in RFS between 5.5 and 9.5 months using a one-sided log rank test. Participants must have had R0/R1 resection &lt;90 days prior to registration, and no prior systemic therapy (adjuvant radiation allowed), ECOG 0/1, no uncontrolled significant autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. Results: From 9/17 to 8/21, 44 patients were approached at 6 centers. Of these 9 were ineligible, and 35 were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) had adjuvant radiation prior to enrollment. As of Dec 2021, 31 patients have completed the treatment phase. Of the 35 patients treated on study, 20 patients have recurred (7 local, 5 distant, 3 regional, 5 sites unconfirmed), 6 stopped therapy due to adverse effects, and 8 have died. The mean age of patients was 65.8 years and 21 (60.0%) were female. The primary site of disease was vulvovaginal N=12 (32.4%) patients, sinonasal N= 11 (29.7%), anorectal N= 9 (24.3%) and other site N= 5 (13.5%). Adjuvant radiation had been given in 7 pts. Driver mutations were rare, with only 3 (8.6%) patients having a KIT mutation, and one patient (2.9%) each having a NRAS or BRAF mutation. RFS rates at 1 and 2 years were 50% (95% CI 31-66%) and 37% (95% CI 19-55%), with OS rates at 1 and 2 years of 87% (95% CI 68-95%) and 68% (95% CI 46-83%). Median RFS was 10.3 m (95% CI5.7-25.8). Most common grade 3 adverse events were diarrhea (14%), hypertension (14%), hyponatremia (11%), with no grade 4/5 toxicities. Conclusions: Flip dose ipilimumab and nivolumab after resection is associated with outcomes improved over previously reported outcomes in the absence of therapy. Long term follow up is ongoing as are subgroup analyses and correlative studies. Clinical trial information: NCT03241186.